Low levels of HIV-1 drug resistance mutations in patients who achieved viral re-suppression without regimen switch: a retrospective study.
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ABSTRACT:
SUBMITTER: Onwuamah CK
PROVIDER: S-EPMC6971913 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Residual systemic inflammation, which is associated with non-AIDS clinical outcomes, may persist despite viral suppression. We assessed the effect of antiretroviral therapy (ART) adherence interruptions on systemic inflammation among Ugandans living with HIV who were virally suppressed. SETTING:We evaluated adults initiating first-line ART at a regional referral hospital clinic in Mbarara, Uganda. METHODS:Plasma concentrations of interleukin-6 (IL-6), D-dimer, soluble sCD14, sCD163, the kynurenine/tryptophan (K/T) ratio, and CD8 T-cell activation (HLA-DR/CD38 coexpression) were measured at baseline and 6 months after ART initiation among participants who achieved viral suppression (<400 copies/mL) at 6 months. ART adherence was monitored electronically. Time spent in an adherence interruption was computed as the percentage of days when the running average adherence was ?10%. We fit adjusted linear regressions to evaluate the effect of time spent in an interruption on the log-transformed plasma concentrations of the inflammation biomarkers. RESULTS:Of 282 participants, 70% were women, and the median age was 34 years. At baseline, median CD4 and median log viral load were 135 cells per microliter and 5.1 copies per milliliter, respectively. In the adjusted analysis, a running average adherence of <10% was associated with higher sCD14 (+3%; P < 0.008), sCD163 (+5%; P = 0.002), D-dimer (+10%; P = 0.007), HLA-DR/CD8 (+3%; P < 0.025), IL-6 (+14%; P = 0.008), and K:T ratio (+5%; P = 0.002). These findings were largely robust to adjustment for average adherence, as well as higher thresholds of running average adherence, albeit with decreased statistical significance. CONCLUSIONS:Increased time spent in adherence interruptions is associated with increased levels of inflammation, despite viral suppression above and beyond average adherence.
| S-EPMC6820698 | biostudies-literature
Project description:We have previously reported on HIV-1 infected patients who fail anti-retroviral therapy but manage to re-suppress without a regimen change despite harbouring major drug resistance mutations. Here we explore phenotypic drug resistance in such patients in order to better understand this phenomenon. Patients (n = 71) failing a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, but who subsequently re-suppressed on the same regimen, were assessed for HIV-1 genotypic drug resistance through Sanger sequencing. A subset (n = 23) of these samples, as well as genotypically matched samples from patients who did not re-suppress (n = 19), were further assessed for phenotypic drug resistance in an in vitro single cycle assay. Half of the patients (n = 36/71, 51%) harboured genotypic drug resistance, with M184V (n = 18/36, 50%) and K103N (n = 16/36, 44%) being the most prevalent mutations. No significant difference in the median time to re-suppression (31-39 weeks) were observed for either group (p = 0.41). However, re-suppressors with mutant virus rebounded significantly earlier than those with wild-type virus (16 vs. 33 weeks; p = 0.014). Similar phenotypic drug resistance profiles were observed between patients who re-suppressed and patients who failed to re-suppress. While most remained susceptible to stavudine (d4T) and zidovudine (AZT), both groups showed a reduced susceptibility to 3TC and NNRTIs. HIV- 1 infected patients on an NNRTI-based regimen can achieve viral re-suppression on the same regimen despite harbouring viruses with genotypic and phenotypic drug resistance. However, re-suppression was less durable in those with resistance, reinforcing the importance of appropriate regimen choices, ongoing viral load monitoring and adherence counselling.
| S-EPMC7302689 | biostudies-literature
Project description:Stably suppressed viremia during ART is essential for establishing reliable simian models for HIV/AIDS. We tested the efficacy of a multidrug ART (highly intensified ART) in a wide range of viremic conditions (10³-10?) viral RNA copies/mL) in SIVmac251-infected rhesus macaques, and its impact on the viral reservoir. Eleven macaques in the pre-AIDS stage of the disease were treated with a multidrug combination (highly intensified ART) consisting of two nucleosidic/nucleotidic reverse transcriptase inhibitors (emtricitabine and tenofovir), an integrase inhibitor (raltegravir), a protease inhibitor (ritonavir-boosted darunavir) and the CCR5 blocker maraviroc. All animals stably displayed viral loads below the limit of detection of the assay (i.e. <40 RNA copies/mL) after starting highly intensified ART. By increasing the sensitivity of the assay to 3 RNA copies/mL, viral load was still below the limit of detection in all subjects tested. Importantly, viral DNA resulted below the assay detection limit (<2 copies of DNA/5*10? cells) in PBMCs and rectal biopsies of all animals at the end of the follow-up, and in lymph node biopsies from the majority of the study subjects. Moreover, highly intensified ART decreased central/transitional memory, effector memory and activated (HLA-DR?) effector memory CD4? T-cells in vivo, in line with the role of these subsets as the main cell subpopulations harbouring the virus. Finally, treatment with highly intensified ART at viral load rebound following suspension of a previous anti-reservoir therapy eventually improved the spontaneous containment of viral load following suspension of the second therapeutic cycle, thus leading to a persistent suppression of viremia in the absence of ART. In conclusion, we show, for the first time, complete suppression of viral load by highly intensified ART and a likely associated restriction of the viral reservoir in the macaque AIDS model, making it a useful platform for testing potential cures for AIDS.
| S-EPMC3380955 | biostudies-literature
Project description:GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine.Trial registrationclinicaltrials.gov NCT01378156.
| S-EPMC5053438 | biostudies-literature
Project description:BackgroundHigh rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second-line ART requires clarification.MethodsUsing prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second-line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression.ResultsOne hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/µL (interquartile range [IQR], 77-263) and 4.3 log10 copies/mL (IQR, 3.8-4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and ? 1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL.ConclusionsNonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure.
| S-EPMC3923537 | biostudies-literature
Project description:IntroductionAiming to reach UNAIDS 90-90-90 targets, nearly all sub-Saharan African countries have expanded antiretroviral therapy (ART) to all people living with HIV (PLWH) (Treat All). Few published data exist on viral load testing and viral suppression under Treat All in this region. We assessed proportions of patients with available viral load test results and who were virally suppressed, as well as factors associated with viral suppression, among PLWH in 10 Rwandan health centres after Treat All implementation.MethodsCross-sectional study during 2018 of adults (≥15 years) engaged in HIV care at 10 Rwandan health centres. Outcomes were being on ART (available ART initiation date in the study database, with no ART discontinuation prior to 1 January 2018), retained on ART (≥2 post-ART health centre visits ≥90 days apart during 2018), available viral load test results (viral load measured in 2018 and available in study database) and virally suppressed (most recent 2018 viral load <200 copies/mL). We used modified Poisson regression models accounting for clustering by health centre to determine factors associated with being virally suppressed.ResultsOf 12,238 patients, 7050 (58%) were female and 1028 (8%) were aged 15 to 24 years. Nearly all patients (11,933; 97%) were on ART, of whom 11,198 (94%) were retained on ART. Among patients retained on ART, 10,200 (91%) had available viral load results; of these 9331 (91%) were virally suppressed. Viral suppression was less likely among patients aged 15 to 24 compared to >49 years (adjusted prevalence ratio (aPR): 0.83, 95% CI 0.76 to 0.90 and those with pre-ART CD4 counts of <200 compared to ≥500 cells/mm3 (aPR: 0.92, 95% CI 0.90 to 0.93). There was no statistically significant difference in viral suppression among patients who entered after Treat All implementation compared to those who enrolled before 2010 (aPR 0.98, 95% CI 0.94 to 1.03).ConclusionsIn this large cohort of Rwandan PLWH receiving HIV care after Treat All implementation, patients in study health centres have surpassed the third UNAIDS 90-90-90 target. To ensure all PLWH fully benefit from ART, additional efforts should focus on improving ART adherence among younger persons.
| S-EPMC7293767 | biostudies-literature
Project description:BackgroundSolid-organ transplantation due to end-stage organ disease is increasingly performed in people living with HIV. Despite improved transplant outcomes, management of these patients remains challenging due to higher risk for allograft rejection, infection and drug-drug interactions (DDIs). Complex regimens for multi-drug resistant HIV-viruses may cause DDIs particularly if the regimen contains drugs such as ritonavir or cobicistat.Case presentationHere we report on a case of an HIV-infected renal transplant recipient on long-term immunosuppressive therapy with mycophenolate mofetil and tacrolimus dosed at 0.5 mg every 11 days due to the co-administration of a darunavir/ritonavir containing antiretroviral regimen. In the presented case the pharmacokinetic booster was switched from ritonavir to cobicistat for treatment simplification. A close monitoring of tacrolimus drug levels was performed in order to prevent possible sub- or supratherapeutic tacrolimus trough levels. A progressive decrease in tacrolimus concentrations was observed after switch requiring shortening of tacrolimus dosing interval. This observation was unexpected considering that cobicistat is devoid of inducing properties.ConclusionsThis case highlights the fact that the pharmacokinetic boosters ritonavir and cobicistat are not fully interchangeable. Therapeutic drug monitoring of tacrolimus is warranted to maintain levels within the therapeutic range.
| S-EPMC10163738 | biostudies-literature
Project description:ObjectiveThe proportion of people living with HIV with suppressed viral load is a key indicator of the HIV care continuum. We explored how this proportion varied depending on how it was calculated.DesignObservational cohort study.MethodsWe calculated the proportion of the Johns Hopkins HIV Clinical Cohort who were virally suppressed each year, 2010-2018, based on different denominators; thresholds for suppression (≤20, ≤50, ≤200, or ≤400 copies/ml); and strategies for summarizing multiple viral load measurements (we classified persons as suppressed if they had any lab, ≥50% of labs, last lab, or all labs below the threshold). We also calculated 5-year risk of all-cause mortality associated with each classification of viral suppression.ResultsThree thousand eleven persons contributed 60 858 viral load values to this analysis. Proportion classified as virally suppressed ranged from 51.8 to 92.5%, depending on the definition used and persons included in the calculation. Requiring more labs below the threshold; using a lower threshold; and assuming persons lost to follow-up were not suppressed (stricter definitions) resulted in a lower proportion estimated to be suppressed. Suppression by stricter definitions were associated with better 5-year survival.DiscussionThe proportion suppressed varied greatly as a function of the subset of persons in whom it was calculated, the threshold used for suppression, and the way multiple viral loads per person per year were summarized. Measures of durable viral suppression, and low-level viremia (20-400 copies/ml), should be considered in describing the health of people with HIV, in addition to the standard estimates of suppression.
| S-EPMC8327702 | biostudies-literature
Project description: Not available
| S-EPMC8530261 | biostudies-literature
Project description:BackgroundMany HIV-infected African children gained access to antiretroviral treatment (ART) through expansion of PEPFAR programs since 2004 and introduction of "Test and Treat" WHO guidelines in 2015. As ART access increases and children transition from adolescence to adulthood, treatment failure is inevitable. Viral load (VL) monitoring in Uganda was introduced in 2016 replacing clinical monitoring. However, there's limited data on the comparative effectiveness of these two strategies among HIV-infected children in resource-limited settings (RLS).MethodsHIV-infected Ugandan children aged 1-12 years from HIV-care programs with > 1 year of first-line ART using only immunologic and clinical criteria to monitor response to treatment were screened in 2010. Eligible children were stratified by VL ≤ 400 and > 400 copies/ml randomized to clinical and immunological (control) versus clinical, immunological and VL monitoring to determine treatment failure with follow-up at 12, 24, 36, and 48 weeks. Plasma VL was analyzed retrospectively for controls. Mixed-effects logistic regression models were used to compare the prevalence of viral suppression between study arms and identify factors associated with viral suppression.ResultsAt baseline all children (n = 142) were on NNRTI based ART (75% Nevirapine, 25% efavirenz). One third of ART-experienced children had detectable VL at baseline despite high CD4%. Median age was 6 years (interquartile range [IQR]: 5-9) and 43% were female. Overall, the odds of viral suppression were not different between study arms: (arm by week interaction, p = 0.63), adjusted odds ratio [aOR]: 1.07; 95%CI: 0.53, 2.17, p = 0.57) and did not change over time (aOR: 0 vs 24 week: 1.15; 95% CI: 0.91, 1.46, p = 0.24 and 0 vs 48 weeks: 1.26; 95%CI: 0.92, 1.74, p = 0.15). Longer duration of a child's ART exposure was associated with lower odds of viral suppression (aOR: 0.61; 95% CI: 0.42, 0.87, p < .01). Only 13% (9/71) of children with virologic failure were switched to second-line ART, in spite of access to real-time VL.ConclusionWith increasing ART exposure, viral load monitoring is critical for early detection of treatment failure in RLS. Clinicians need to make timely informed decisions to switch failing children to second-line ART.Trial registrationClinicalTrials.gov NCT04489953 , 28 Jul 2020. Retrospectively registered. ( https://register.clinicaltrials.gov ).
| S-EPMC7983217 | biostudies-literature